ABSTRACT

Tumors are composed of heterogeneous phenotypes, each having different sensitivities to the microenvironment. One microenvironment characteristic – matrix stiffness – helps to regulate malignant transformation and invasion in mammary tumors, but its influence on oral squamous cell carcinoma (OSCC) is unclear. We observed that, on stiff matrices, a highly invasive OSCC cell line (SCC25) comprising a low E-cad to N-cad ratio (InvH/E:NL; SCC25) had increased migration velocity and decreased adhesion strength compared to a less invasive OSCC cell line (Cal27) with high E-cad to N-cad ratio (InvL/E:NH; Cal27). However, InvL/E:NH cells acquire a mesenchymal signature and begin to migrate faster when exposed to prolonged time on a stiff niche, suggesting that cells can be mechanically conditioned. Owing to increased focal adhesion assembly, InvL/E:NH cells migrated faster, which could be reduced when increasing integrin affinity with high divalent cation concentrations. Mirroring these data in human patients, we observed that collagen organization, an indicator of matrix stiffness, was increased with advanced disease and correlated with early recurrence. Consistent with epithelial tumors, our data suggest that OSCC cells are mechanically sensitive and that their contribution to tumor progression is mediated in part by this sensitivity.

The authors declare no competing interests. Funding for this work was provided by the National Institutes of Health (grant numbers: R01CA206880 to A.J.E., R21CA217735 to A.J.E., T32AR060712 to A.K. and F32HL126406 to J.K.P.) as well as by the National Science Foundation (grant number: 1463689 to A.J.E.) and the Graduate Research Fellowship program (A.K.). Additional fellowship support was provided the Brazilian Federal Agency for Support and Evaluation of Graduate Education award (grant number: 88881.135357/2016-01 to B.F.M.) and the ARCS/Roche Foundation Scholarship Award Program in Life Sciences (A.K.) Deposited in PMC for release after 12 months.

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